Cancer vaccines have been effective for inducing T cell responses in patients with melanoma and other cancers, but clinical impact has been limited. Most cancer vaccines have been designed to induce CD8+ T cell responses to cancer antigens, but a growing body of data demonstrates that CD4+ ?helper? T cells have pivotal roles in anticancer immunity. We have found that a vaccine designed to stimulate CD4+ T cells induces Th1-dominant CD4+ helper T cells in most melanoma patients. In addition, this vaccine, comprised of a mixture of 6 intermediate length (14-23 amino acids) melanoma ?helper? peptides (6MHP), have had clinical activity, durable in some patients, and there has been significant correlation between CD4+ helper T cell response and patient survival in two separate clinical trials. Until recently, the focus of these vaccines has been on T cell responses. However, we have recently examined the induction of antibody (Ab) to the peptides and found high titer circulating IgG responses that are associated with significantly better patient survival. The Ab response also was associated with a helper T cell response, but the best clinical outcome was for those with both Ab and T cell responses. It is not known whether Ab induced by melanoma peptide vaccines participates in antitumor activity or is just a biomarker of immune activation. It also is not clear to what extent various vaccine adjuvants may augment or inhibit these Ab responses. The favorable clinical outcome associated with the Ab responses, and especially the combination of Ab and T cell responses, favors the broad hypothesis that the Ab responses may contribute to clinical benefit of 6MHP vaccines. Since clinical trials of peptide vaccines have largely ignored the presence and functional significance of Ab responses to peptide vaccines, it is both significant and novel to determine the immunologic and anti-cancer effects of peptide-induced antibodies. We hypothesize that Abs to 6MHP bind antigen and create large immune complexes (ICs) that facilitate delivery to antigen-presenting cells (APC) and support internalization and cross-presentation by dendritic cells (DC) and B cells via the Fc?R and complement receptor 2 (CR2), thus augmenting antigen presentation and antitumor activity. We also hypothesize that toll-like receptor (TLR) agonists may increase Ab responses to 6MHP vaccines and may modulate the isotype, IgG subtypes, and induction of memory B cells. Specific aims are: Aim 1. To assess the impact of vaccine adjuvants on Ab response to peptides in melanoma vaccines and on induction of memory B cells; Aim 2. To determine the nature of immune complexes (ICs) formed to peptides in the vaccines and whether they facilitate FcR-mediated uptake and presentation by APC.